Electrical stimulation (ES) is a treatment for swallowing impairment (dysphagia) that uses surface electrodes on the anterior neck to repeatedly contract and strengthen swallowing musculature without evoking swallows. This treatment approach is generally avoided in ALS patients due to concerns over rapid muscle fatigue that may further compromise swallowing, breathing, and airway protection. However, swallowing is a sensorimotor reflex that relies on several "upstream" sensory, motor, and interneuron components that are also affected by ALS. We hypothesize that ES can be optimized for ALS by selectively stimulating the superior laryngeal nerve (SLN) to activate and treat the entire swallow reflex circuitry, rather than only the swallowing muscles. Our rationale is based on general knowledge that SLN stimulation reliably evokes swallowing in experimental studies. Here, our translational work establishes a safe and reliable ES-SLN protocol in a mouse model of ALS with dysphagia, and then adapts the protocol for use in humans. For protocol development, ALS mice (transgenic SOD1-G93A) underwent an invasive survival surgery at 6 months of age (clinical disease onset) for 30 minutes of direct ES-SLN based on our prior work: 40 Hz; anodal, charge balanced rectangular pulses (400 µs pulse width, 400 µs interphase delay); up to 800 uA intensity and continuous trains of 20-seconds ON, 10-seconds OFF. Respiratory rate was monitored via an abdominal pneumatic sensor. Swallowing function was assessed via monthly videofluoroscopy. For translation to humans we used a noninvasive transcutaneous ES (tES) approach in five healthy adults (18-30 years; 3 F, 2 M) using identical stimulus parameters as mice, except with a shorter pulse duration (100 µs pulse width, 25 μs interphase delay) to eliminate perceived muscle fatigue and higher stimulus intensity (up to 10 mA). Physiological monitoring (pulse oximetry, respiratory and heart rate) occurred throughout the 30-minute session. Results showed that direct ES-SLN in mice consistently evoked 2-4 swallows per 20 second stimulus train without decay or adverse effects on respiratory rate (p>0.05). Moreover, this single treatment session nearly preserved lick and swallow rates at disease end stage. In humans, tES-SLN reliably evoked 3-6 saliva swallows per 20 second stimulus train without decay or adverse effects on physiological measures (p>0.05). However, trials were successful only in females likely due to differences in male anatomy and electrical impedance that we are troubleshooting. This preliminary work demonstrates ES can be adapted for targeted, noninvasive SLN stimulation to evoke swallowing in humans. Moreover, our preliminary work with ALS mice suggests an untapped therapeutic benefit of ES-SLN, which provides rationale for proceeding with clinical trials for ALS patients as well as other neurological diseases. Continued investigations in mice will be essential to understand the treatment mechanisms of SLN stimulation for further optimization.

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